Methods of preparing aripiprazole crystalline forms

ABSTRACT

The invention encompasses aripiprazole crystalline forms, methods of preparing the same, and pharmaceutical compositions having aripiprazole crystalline forms.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/015,068, filed Dec. 16, 2004, which claims the benefit of U.S.provisional Application No. 60/530,297, filed Dec. 16, 2003; U.S.provisional Application No. 60/533,831, filed Dec. 30, 2003; U.S.provisional Application No. 60/618,404, filed Oct. 13, 2004; and U.S.provisional Application No. 60/618,960, filed Oct. 14, 2004.

FIELD OF THE INVENTION

The invention encompasses crystalline forms of aripiprazole forms andmethods of preparing them.

BACKGROUND OF THE INVENTION

Schizophrenia is the most common type of psychosis caused by excessiveneurotransmission activity of the dopaminergic nervous system in thecentral nervous system. A number of drugs which block theneurotransmission of dopaminergic receptor in the central nervous systemhave been developed for use in treating schizophrenia. Among the drugsdeveloped are phenothiazine-type compounds such as chlorpromazine,butyrophenone-type compounds such as haloperidol, and benzamide-typecompounds such as sulpiride. These drugs improve so-called positivesymptoms in the acute period of schizophrenia such as hallucinations,delusions, and excitations. Many drugs for treating schizophrenia,however, are not effective for improving the so-called negative symptomswhich are observed in the chronic period of schizophrenia such asapathy, emotional depression, and hypopsychosis. The drugs currentlyused produce undesirable side effects such as akathisia, dystonia,Parkinsonism dyskinesia, and late dyskinesia, by blocking theneurotransmission of dopaminergic receptor in the striate body. Drugsthat improve both the negative and positive symptoms of schizophreniabut diminish the undesirable side effect of schizophrenia areparticularly desirable.

Aripiprazole is a pyschotropic drug that exhibits high affinity fordopamine D₂ and D₃, serotonin 5-HT_(1A) and 5-HT_(2A) receptors;moderate affinity for dopamine D₄, serotonin 5-HT_(2C) and 5-HT₇,α₁-adrenergic and histamine H₁ receptors; and moderate affinity for theserotonin reuptake site. Aripiprazole has no appreciable affinity forcholinergic muscarinic receptors. The mechanism of action ofaripiprazole, as with other drugs having efficacy in schizophrenia, isunknown. It has been proposed, however, that the efficacy ofaripiprazole is mediated through a combination of partial agonistactivity at D₂ and 5-HT_(1A) receptors and antagonist activity at5-HT_(2A) receptors.

Japanese Patent Kokai No. 02-191256 discloses that anhydride crystals ofaripiprazole are typically manufactured by recrystallization ofanhydride aripiprazole from ethanol or by heating aripiprazole hydrateat a temperature of 80° C. According to WO 03/26659, anhydridearipiprazole prepared by these methods is significantly hygroscopic.

The Proceedings of the 4^(th) Japanese-Korean Symposium on SeparationTechnology (Oct. 6-8, 1996) disclosed that aripiprazole anhydridecrystals may exist as Type-I and Type-II crystals. Type-I aripiprazolecrystals can be prepared by recrystallizing aripiprazole from an ethanolsolution or by heating aripiprazole hydrate at 80° C. Type-IIaripiprazole crystals can be prepared by heating the Type-I crystals at130° C. to 140° C. for 15 hours. This process is not easily applied toan industrial scale preparation of anhydride aripiprazole.

PCT publication WO 03/26659 discloses the preparation of anhydrousaripiprazole Type I and crystalline forms Form A, B, C, and D.Typically, the process for preparing the crystalline forms comprisesheating crystalline anhydrous aripiprazole. The process, however, iscumbersome because it requires crystalline anhydrous aripiprazole as thestarting material. The process in the PCT publication can only becarried out after the preparation, isolation, and purification ofaripiprazole. Thus, only after performing the additional steps may oneheat the crystalline anhydrous aripiprazole to obtain the desiredcrystalline forms of aripiprazole. Additionally, drying or heating mayaffect the distribution of crystalline forms and/or crystalline purity,if drying causes crystalline transformation from one crystalline form toanother.

Alternate crystalline structures possessing the stability andmanufacturing advantages of anhydrous aripiprazole are highly desired.Likewise, methods for making aripiprazole without additional steps andcost also are necessary.

SUMMARY OF THE INVENTION

The invention encompasses anhydrous aripiprazole crystalline forms whichare non-hygroscopic and which maintain compound stability duringstorage, and methods for preparing the non-hygroscopic aripiprazolecrystalline forms.

One embodiment of the invention encompasses a crystalline anhydrousaripiprazole Form I characterized by X-ray powder diffraction peaks at16.8, 19.6, 20.6, 22.3, and 25.1 degrees two-theta, ±0.2 degreestwo-theta.

Another embodiment of the invention encompasses aripiprazole Form IIcharacterized by X-ray powder diffraction peaks at 16.5, 18.7, 21.9,22.4, and 23.5 degrees two-theta, +0.2 degrees two-theta.

Another embodiment of the invention encompasses substantially purecrystalline aripiprazole Form II. For example, substantially pure FormII may encompass Form II having less than 40% by weight of othercrystalline aripiprazole forms and preferably no more than 10% by weightof other crystalline aripiprazole forms.

Particular embodiments of the invention encompass Form II having no morethan 40% by weight of crystalline compound 1, crystalline compound 2,Form C, or Form D. In another embodiment, Form II has no more than 30%by weight of crystalline compound 1, crystalline compound 2, Form C, orForm D, preferably no more than 20%, more preferably no more than 10%,and most preferably no more than 5% by weight.

Another embodiment of the invention encompasses crystalline aripiprazoleForm VI characterized by X-ray powder diffraction peaks at 17.6, 17.8,20.6, and 24.9 degrees two-theta, ±0.2 degrees two-theta.

Yet another embodiment of the invention encompasses aripiprazolecrystalline Form VIII characterized by X-ray powder diffraction peaks at4.4, 8.7, 20.8, 21.6, and 26.0 degrees two-theta, ±0.2 degreestwo-theta. Another embodiment of the invention encompasses crystallinearipiprazole Form X characterized by X-ray powder diffraction peaks at18.2, 22.4, 22.8, and 24.3 degrees two-theta, +0.2 degrees two-theta.

Yet another embodiment of the invention encompasses aripiprazolecrystalline Form XI characterized by X-ray powder diffraction peaks at5.9, 18.0, 20.5, 24.5, and 25.1 degrees two-theta, ±0.2 degreestwo-theta.

Another embodiment of the invention encompasses crystalline aripiprazoleForm XIV characterized by X-ray powder diffraction peaks at 11.0, 23.6,24.7, 25.2, and 29.0 degrees two-theta, ±0.2 degrees two-theta.

Another embodiment of the invention encompasses crystalline aripiprazoleForm XIX characterized by X-ray powder diffraction peaks at 17.4, 18.7,20.0, 23.3, and 24.5 degrees two-theta, ±0.2 degrees two-theta.

Another embodiment of the invention encompasses crystalline aripiprazoleForm XX characterized by X-ray powder diffraction peaks at 19.6, 20.4,20.8, 22.1, and 24.5 degrees two-theta, +0.2 degrees two-theta.

Another embodiment of the invention encompasses a method of preparingForm II by slurrying crystalline aripiprazole compound 2 in acetone atroom temperature to form Form II, and collecting the Form II.

Yet another embodiment of the invention encompasses methods forpreparing crystalline aripiprazole comprising dissolving aripiprazole ina solvent to form a mixture, heating the mixture from about 40° C. toabout 132° C., cooling the mixture to form a aripiprazole precipitate,and collecting the precipitate.

A second method of preparing crystalline aripiprazole comprisesdissolving aripiprazole in a solvent to form a mixture, heating themixture to the solvent's boiling point until aripiprazole dissolves,adding a co-solvent to precipitate aripiprazole, cooling the mixture toabout room temperature to about 4° C., and collecting the precipitate.The second method may further comprise cooling the aripiprazole solventmixture to the boiling point of the co-solvent before adding theco-solvent if the boiling point of the co-solvent is lower than theboiling point of the solvent.

One embodiment of the invention encompasses methods of preparing Form Icomprising providing aripiprazole crystalline Form X and drying Form Xto obtain Form I.

Another embodiment of the invention encompasses methods of preparingcrystalline Form II comprising providing aripiprazole crystallinecompound 1 and drying compound 1 to obtain Form II.

Yet another embodiment of the invention encompasses methods of preparingcrystalline Compound 2 comprising providing at least one of aripiprazoleForm D, Form X, Form XI, Form XII, or Form XIX, and heating thearipiprazole to obtain Compound 2.

Yet another embodiment of the invention encompasses methods of preparingcrystalline Compound 2 comprising providing Form X, and drying thearipiprazole to obtain Compound 2.

Another embodiment of the invention encompasses methods of preparingcrystalline Form C comprising providing Form II, crystalline Compound 1,or crystalline Compound 2, and heating aripiprazole to obtain Form C.

Yet another embodiment encompasses methods of preparing Form Dcomprising providing aripiprazole crystalline Compound 1, crystallineCompound 2, or Form XIV, and drying the aripiprazole to obtain Form D.

Another embodiment of the invention encompasses methods of preparing amixture of crystalline Compound 2 and Compound 1 comprising providingaripiprazole Form XI and drying Form XI to obtain a mixture ofaripiprazole crystalline Compound 2 and crystalline Compound 1.

Yet another embodiment of the invention encompasses methods of preparinga mixture of Form D, Compound 1, and crystalline Compound 2 comprisingproviding a mixture of Form D and Compound 1, and drying the mixture toobtain a mixture of Form D, Compound 1, and crystalline Compound 2.

Other embodiments of the invention encompass pharmaceutical compositionscomprising aripiprazole crystalline forms of the invention and methodsof treating schizophrenia using these pharmaceutical compositions.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the powder X-ray diffraction pattern for Form I.

FIG. 2 illustrates the powder X-ray diffraction pattern for Form II.

FIG. 3 illustrates the powder X-ray diffraction pattern for Form VI.

FIG. 4 illustrates the powder X-ray diffraction pattern for Form VIII.

FIG. 5 illustrates the powder X-ray diffraction pattern for Form X.

FIG. 6 illustrates the powder X-ray diffraction pattern for Form XI.

FIG. 7 illustrates the powder X-ray diffraction pattern for Form XII.

FIG. 8 illustrates the powder X-ray diffraction pattern for Form XIV.

FIG. 9 illustrates the powder X-ray diffraction pattern for Form XIX.

FIG. 10 illustrates the powder X-ray diffraction pattern for Form XX.

FIG. 11 illustrates the differential scan calorimetry analysis for FormI.

FIG. 12 illustrates the differential scan calorimetry analysis for FormII.

FIG. 13 illustrates the differential scan calorimetry analysis for FormVI.

FIG. 14 illustrates the differential scan calorimetry analysis for FormVIII.

FIG. 15 illustrates the differential scan calorimetry analysis for FormX.

FIG. 16 illustrates the differential scan calorimetry analysis for FormXI.

FIG. 17 illustrates the differential scan calorimetry analysis for FormXIX.

FIG. 18 illustrates the differential scan calorimetry analysis for FormXX.

FIG. 19 illustrates the powder X-ray diffraction pattern for Form IIobtained by slurrying aripiprazole crystalline Compound 2 with acetone.

FIG. 20 illustrates the powder X-ray diffraction pattern for Form IIhaving 10% of Form C.

FIG. 21 illustrates the powder X-ray diffraction pattern for Form IIhaving 20% of Form C.

FIG. 22 illustrates the powder X-ray diffraction pattern for Form IIhaving 30% of Form C.

FIG. 23 illustrates the powder X-ray diffraction pattern for Form IIhaving 40% of Form C.

FIG. 24 is a staggered figure illustrating the X-ray diffractionpatterns for crystalline Compound 1 and crystalline Compound 2.

DETAILED DESCRIPTION OF THE INVENTION

The time and expense required to prepare aripiprazole on an industrialscale is decreased by using the anhydrous aripiprazole crystals of theinvention. Specifically, the anhydrous aripiprazole forms of theinvention diminish the adherence of aripiprazole to equipment duringindustrial preparation, which in turn diminishes the necessity ofspecial handling techniques to maintain the equipment and anhydrousaripiprazole. The invention also encompasses aripiprazole crystallineforms that can be prepared directly by slurrying, rather than by heatinga preexisting hydrate crystal form, thereby eliminating unnecessaryprocess steps during manufacture. The invention also encompasses methodsof preparing crystalline Compound 2 by crystallization and shorterdrying processes than the drying process for aripiprazole crystallineforms disclosed in WO 03/26659.

The aripiprazole forms encompassed by the invention may be characterizedby at least one of Karl Fisher or TGA, X-Ray power diffraction (XRD), ordifferential scan calorimetry (DSC).

As used herein, the term “anhydrous” refers to aripiprazole crystalforms with less than about 0.5% moisture.

One embodiment of the invention encompasses a crystalline anhydrousaripiprazole form, herein defined as Form I, having about 0.7% moistureby weight as measured by Karl Fisher or TGA. Form I may be characterizedby X-ray powder diffraction peaks at 16.8, 19.6, 20.6, 22.3, and 25.1degrees two-theta, ±0.2 degrees two-theta. Form I may be characterizedfurther by X-ray powder diffraction peaks at 11.3, 12.3, 14.6, 15.2,17.9, 22.8, and 23.6 degrees two-theta, +0.2 degrees two-theta. Form Imay be characterized also by a melting endotherm at about 139° C. toabout 140° C. (about 90 J/g melting enthalpy) as measured bydifferential scanning calorimetry (DSC). Form I may be substantiallyidentified by either the XRD pattern of FIG. 1 or the DSC of FIG. 11.

Another embodiment of the invention is a crystalline aripiprazole form,herein defined as Form II, having about 0.3% moisture by weight asmeasured by Karl Fisher or TGA. Form II may be characterized by X-raypowder diffraction peaks at 16.5, 18.7, 21.9, 22.4, and 23.5 degreestwo-theta, +0.2 degrees two-theta. Form II may be characterized furtherby X-ray powder diffraction peaks at 10.2, 11.8, 20.0, 20.7, 26.2, 27.3,and 29.0 degrees two-theta, ±0.2 degrees two-theta. Form II may becharacterized also by DSC showing a broad and small endotherm in therange of about 100° C. to about 130° C. and a melting endotherm at about148° C. to about 150° C. The latter indicating a transformation to FormC. Form II may be substantially identified by either the XRD pattern ofFIG. 2 or the DSC of FIG. 12.

Another embodiment of the invention encompasses substantially pure FormII. As used herein, the term “substantially pure” refers to Form IIhaving less than 40% of other aripiprazole crystalline forms and morepreferably no more than 10% by weight of other aripiprazole crystallineforms.

A particular embodiment of the invention encompasses Form II having nomore than 40% by weight of crystalline Compound 1, crystalline Compound2, Form C, or Form D. In another particular embodiment, Form II has nomore than 30% by weight of crystalline Compound 1, crystalline Compound2, Form C, or Form D, preferably no more than 20%, more preferably nomore than 10%, and most preferably no more than 5% by weight.

As used herein, “crystalline compound 1” refers to an aripiprazolecrystalline form characterized by X-ray powder diffraction peaks at15.5, 19.5, 22.6, 24.9, and 30.6 degrees two-theta, 0.2 degreestwo-theta. As used herein, “crystalline compound 2” refers to anaripiprazole crystalline form characterized by X-ray powder diffractionpeaks at 8.8, 14.5, 17.8, 20.5, and 22.2 degrees two-theta, 0.2 degreestwo-theta.

FIG. 20 illustrates an X-ray diffraction pattern of Form II having 10%Form C by weight. FIG. 21 illustrates an X-ray diffraction pattern ofForm II having 20% Form C by weight. FIG. 22 illustrates an X-raydiffraction pattern of Form II having 30% Form C by weight. FIG. 23illustrates an X-ray diffraction pattern Form II having 40% Form C byweight.

Another embodiment of the invention encompasses is a crystallinearipiprazole form, herein defined as Form VI, having about 0.2% moistureby weight as measured by TGA. Form VI may be characterized by X-raypowder diffraction peaks at 17.6, 17.8, 20.6, and 24.9 degreestwo-theta, +0.2 degrees two-theta. Form VI may be characterized furtherby X-ray powder diffraction peaks at 23.7, 27.0, and 31.2 degreestwo-theta, 0.2 degrees two-theta. The typical DSC of Form VI shows twoendotherm peaks, a first peak at about 105° C., and a second peak atabout 110° C. Aripiprazole Form VI may be substantially identified byeither the XRD pattern of FIG. 3 or the DSC of FIG. 13.

Yet another embodiment of the invention is a crystalline aripiprazoleform, herein defined as Form VIII, having a weight loss of about 28% asmeasured by TGA, and a Karl Fisher analysis of about 0.5%. Form VIII maybe characterized by X-ray powder diffraction peaks at 4.4, 8.7, 20.8,21.6, and 26.0 degrees two-theta, ±0.2 degrees two-theta. Form VIII maybe characterized further by X-ray powder diffraction peaks at 13.0,17.3, 19.3, 24.5, 27.4, and 29.2 degrees two-theta, +0.2 degreestwo-theta. The typical DSC of Form VIII shows one endotherm at about 87°C. followed by a broad endotherm. Form VIII may be substantiallyidentified by either the XRD pattern FIG. 4 or the DSC of FIG. 14.

Another embodiment of the invention is a crystalline aripiprazole form,herein defined as Form X, having about 16% moisture by weight. Form Xmay be characterized by X-ray powder diffraction peaks at 18.2, 22.4,22.8, and 24.3 degrees two-theta, +0.2 degrees two-theta. Form X may becharacterized further by X-ray powder diffraction peaks at 15.4, 19.8,23.5, and 29.1 degrees two-theta, ±0.2 degrees two-theta. The typicalDSC of Form X has an endotherm below about 100° C. Additionally, twoendotherms appear at about 136° C. to about 140° C. and at about 147° C.to about 149° C. The first endotherm represents the transformation tocrystalline Compound 2. The second endotherm represent thetransformation to Form C. Form X may be substantially identified byeither the XRD pattern of FIG. 5 or the DSC of FIG. 15.

Yet another embodiment of the invention is a crystalline aripiprazoleform, herein defined as Form XI, having about 14% moisture by weight.Form XI may be characterized by X-ray powder diffraction peaks at 5.9,18.0, 20.5, 24.5, and 25.1 degrees two-theta, ±0.2 degrees two-theta.Form XI may be characterized further by X-ray powder diffraction peaksat 19.0, 19.6, 22.7, 26.4, and 28.3 degrees two-theta, +0.2 degreestwo-theta. The typical DSC of Form XI shows an endotherm below about100° C. and a melting endotherm at about 140° C. due to a transformationto crystalline Compound 2. Form XI may be substantially identified byeither the XRD pattern of FIG. 6 or the DSC of FIG. 16.

Another embodiment of the invention is a crystalline aripiprazole form,herein defined as Form XIV, having about 9% weight loss as measured byTGA, and about 2% water content as measured by Karl Fisher. Form XIV maybe characterized by X-ray powder diffraction peaks at 11.0, 23.6, 24.7,25.2, and 29.0 degrees two-theta, +0.2 degrees two-theta. Form XIV maybe characterized further by X-ray powder diffraction peaks at 12.9,16.5, 18.8, 22.2, 26.3, 27.3, and 28.5 degrees two-theta, ±0.2 degreestwo-theta. Form XIV may be substantially identified by the XRD patternof FIG. 8.

Another embodiment of the invention is a crystalline aripiprazole form,herein defined as Form XIX, having about 6% or less of moisture byweight as measured by Karl Fischer. Form XIX may be characterized byX-ray powder diffraction peaks at 17.4, 18.7, 20.0, 23.3, and 24.5degrees two-theta, +0.2 degrees two-theta. Form XIX may be characterizedfurther by X-ray powder diffraction peaks at 10.8, 11.6, 27.1, 27.7, and28.3 degrees two-theta, +0.2 degrees two-theta. The typical DSC of FormXIX shows two endotherms, one at about 115° C., and one at about 140° C.Form XIX may be substantially identified by either the XRD pattern ofFIG. 9 or the DSC of FIG. 17.

Another embodiment of the invention is a crystalline aripiprazole form,herein defined as Form XX, having about 1.4% to about 5% moisture byweight as measured by Karl Fischer. Form XX may be characterized byX-ray powder diffraction peaks at 19.6, 20.4, 20.8, 22.1, and 24.5degrees two-theta, ±0.2 degrees two-theta. Form XX may be characterizedfurther by X-ray powder diffraction peaks at 10.2, 11.0, 15.6, 17.4,18.2, 25.8, 26.6, and 28.5 degrees two-theta, ±0.2 degrees two-theta.The typical DSC of Form XX shows an endotherm at about 100° C., anendotherm at about 120° C., and multiple transitions between 140° C. and150° C. Form XX may be substantially identified by either the XRDpattern of FIG. 10 or the DSC of FIG. 18.

The invention also encompasses methods of preparing Form I comprisingproviding Form X and drying Form X to obtain Form I.

The invention also encompasses methods of preparing Form II comprisingproviding crystalline Compound 1 and drying crystalline Compound 1 toobtain Form II.

The invention also encompasses a method for preparing Form II byslurrying crystalline Compound 2 in a sufficient amount of acetone forabout one to about 24 hours until to obtain Form II and collecting FormII. Form II obtained by slurrying aripiprazole crystalline Compound 2with acetone is substantially identified by the XRD of FIG. 19.

One of ordinary skill in the art with little or no experimentation caneasily determine the sufficient amount of acetone depending upon theamount of aripiprazole crystalline Compound 2 used during the slurrying.Conditions that affect the amount of acetone include, but are notlimited to, the amount of Form II to be crystallized and the purity ofthe starting crystalline Compound 2. Preferably, crystalline compound 2is slurried for about three hours to about 24 hours, and more preferablyfor about five hours. Optionally, the process may further comprisedrying the collected Form II at 50° C.

Form II may have a maximum particle size of about 300 microns or less.

The invention also encompasses methods for preparing aripiprazolecrystalline Compound 1, crystalline Compound 2, Form D, Form I, Form II,Form VI, Form VIII, Form X, Form XI, or Form XII comprising dissolvingaripiprazole in a solvent to form a mixture, heating the mixture tobetween about 40° C. and 132° C., cooling the mixture to form aprecipitate, and collecting the precipitate. Preferably, the mixture isheated to about the lower of the boiling point of the solvent oraripiprazole's melting point before cooling. The mixture is preferablycooled to about 4° C. for a sufficient amount of time to form aprecipitate. The resulting precipitate may be collected by any methodcommonly known in the art. Optionally, the method may further comprisedrying the precipitate. Example 1 exemplifies the method describedabove. Table 1 summarized the results of the method.

Solvents which may be used in the method of the invention include, butare not limited to, C₃₋₆ ketones, C₁₋₄ nitrites, C₁₋₄ alcohols, C₁₋₆halogenated alkanes, C₁₋₆ amines, C₂₋₈ amides, C₂₋₆ esters, C₂₋₆ ethers,C₁₋₆ sulfoxides, and C₄₋₁₀ aromatics. Preferably, the solvent is atleast one of acetone, acetonitrile, trichloroacetonitrile, methanol,ethanol, n-propanol, isobutanol, propylene glycol, methyl-ethyl-ketone,tetrahydrofuran, DMF, piperidine, pyridine, xylene, toluene,cyclohexanamide, diethylamine, hexylamine, dimethylsulfoxide, ethylacetate, butyl acetate, dichloromethane, dibromomethane, chloroform,1-bromopropane, 1,4-dioxane, 1,2-diaminoethane, 1,4-dibromobutane,isopropanol, 1-butanol, 2-dimethylaminoethanol, cyclopropylmethylketone,or isobutlymethylketone.

The invention also encompasses methods for preparing crystallinecompound 2 comprising dissolving aripiprazole in a solvent to form amixture, heating the mixture to between about 40° C. and 132° C.,cooling the mixture to form a precipitate, and collecting theprecipitate. Preferably, the mixture of aripiprazole and solvent isheated to about the lower of the boiling point of the solvent oraripiprazole's melting point before cooling. The mixture is preferablycooled to about 4° C. for a sufficient amount of time to form aprecipitate. The resulting precipitate may be collected by any methodcommonly known in the art. Optionally, the method may further comprisedrying the precipitate. The method is exemplified in Example 1 andresults are summarized in Table 1.

Solvents which may be used in the invention include, but are not limitedto, C₃₋₆ ketones, C₁₋₄ nitriles, C₁₋₄ alcohols, C₁₋₆ halogenatedalkanes, C₁₋₆ amines, C₂₋₈ amides, C₂₋₆ esters, C₂₋₆ ethers, C₁₋₆sulfoxides, and C₄₋₁₀ aromatics. Preferably, the solvent is at least oneof chloroform, tetrahydrofuran, diethylamine, acetone, acetonitrile,piperidine, butylacetate, or DMF.

The amount of solvent added should be sufficient dissolve the amount ofaripiprazole used. One of ordinary skill in the art with little or noexperimentation can easily determine the sufficient amount of solvent.Conditions that affect the amount of solvent include, but are notlimited to, the amount of aripiprazole to be crystallized and the purityof the starting aripiprazole.

A second method of the invention encompasses preparing crystallineCompound 1, crystalline Compound 2, Form II, Form XII, or Form XIX bydissolving aripiprazole in a solvent to form a mixture, heating themixture to the solvent's boiling point to dissolve aripiprazole, addinga co-solvent to precipitate aripiprazole, cooling the co-solvent mixtureto about room temperature to about 4° C., and collecting theprecipitate. The second method may further comprise cooling the mixturebefore adding the co-solvent if the boiling point of the co-solvent islower than the boiling point of the solvent.

Preferably, the co-solvent mixture is left at about 4° C. for 15 hoursbefore collecting the precipitate. The precipitate may be collected byany method commonly known in the art. Optionally, the process mayfurther comprise drying the precipitate, preferably under reducedpressure of less than about 100 mm Hg at 35° C.

As described above, one of ordinary skill in the art can easilydetermine the amount of solvent necessary to dissolve aripiprazole.Solvents that may be used in the second method of the invention include,but are not limited to, C₂₋₆ esters, C₂₋₆ ethers, methylethylketones, orC₁₋₆ halogenated alkanes. Preferably, the solvent is at least one ofethyl acetate, methylethylketone, chloroform, or tetrahydrofuran.

The co-solvent of the second method should be added in an amountsufficient to precipitate aripiprazole from solution. Co-solvents thatmay be used in the second method of the invention include, but are notlimited to, at least one of water, C₁₋₄ alcohols, C₂₋₆ ether, oracetone. Preferably, the co-solvent is at least one of acetone, water,methanol, ethanol, ether, or 2-propanol.

A second method of preparing aripiprazole crystalline compound 2encompasses dissolving aripiprazole in a solvent to form a mixture,heating the mixture to the solvent's boiling point to dissolvearipiprazole, adding a co-solvent until aripiprazole precipitates,cooling the mixture to about room temperature to about 4° C., andcollecting the precipitated crystalline compound 2. The second methodmay further comprise cooling the aripiprazole solvent mixture beforeadding co-solvent if the boiling point of the co-solvent is lower thanthe boiling point of the solvent.

Preferably, the mixture is left at about 4° C. for 15 hours beforecollecting the precipitated aripiprazole. The precipitate may becollected by any method commonly known in the art. Optionally, theprocess may further comprise drying the precipitate, preferably underreduced pressure of less than about 100 mmHg at 35° C.

As indicated above, one of ordinary skill in the art can easilydetermine the amount of solvent necessary to dissolve aripiprazole.Solvents that may be used in the second method of the invention include,but are not limited to, C₂₋₆ esters, C₂₋₆ ethers, methylethylketones,and C₁₋₆ halogenated alkanes. Preferably, the solvent istetrahydrofuran.

Co-solvent is added in an amount sufficient to precipitate aripiprazolefrom solution. Co-solvents that may be used in the second method of theinvention include, but are not limited to, water, C₁₋₄ alcohols, C₂₋₆ether, or acetone. Preferably, the co-solvent is at list one of acetone,ether, or 2-propanol.

The temperature at which the co-solvent is added depends on the boilingpoint of the co-solvent. If the boiling point for the co-solvent islower than the boiling point of the solvent, then the mixture is cooledto the boiling point of the co-solvent before adding the co-solvent. Ifa precipitate appears while lowering the temperature prior to additionof the co-solvent, then additional solvent should be added in an amountsufficient to dissolve the precipitate. Co-solvent is then added in anamount sufficient to precipitate aripiprazole. Example 2 exemplifies thesecond method. Table 2 summarizes the results of the second method.

The invention also encompasses methods of preparing Form I by dryingForm X under a pressure of less than about 100 mm Hg at 35° C. untilForm I is formed.

The invention also encompasses methods of preparing Form II by dryingcrystalline Compound 1 at a pressure of less than about 100 mm Hg at 35°C. until Form II is formed.

The invention also encompasses methods of preparing crystalline Compound2 comprising providing at least one Form D, Form X, Form XI, Form XII,or Form XIX, and heating to form crystalline Compound 2.

Preferably, the heating step is performed at about 100° C. to about 130°C. for about 30 to about 60 minutes. The preparation of crystallineCompound 2 by heating crystalline Form D, Form X, Form XI, Form XII, orForm XIX may involve an intermediate transformation to Form D. Forexample, crystalline Compound 1 transforms to Form D after heating to100° C. for 60 minutes; however, additional heating at 130° C. for 30minutes completes the conversion of crystalline Compound 1 intocrystalline Compound 2.

The invention also encompasses methods of preparing crystalline Compound2 comprising providing Form XI and drying at a pressure of less thanabout 100 mm Hg at 35° C. to form crystalline Compound 2.

The invention also encompasses methods of preparing crystalline Compound2 by adding Form XII to a reactor at a temperature of about 25° C. toabout 35° C. at a pressure of 100 mm Hg or less, preferably at apressure of 60 mm Hg or less, and gradually increasing the temperatureto about 100° C. or less, while stirring at about 12 rpm, untilcrystalline Compound 2 is obtained. Preferably, the crystalline Compound2 contains no more than 5% of crystalline Form C, Form D, or Form XII.

The invention also encompasses methods of preparing Form C comprisingproviding at least one of Form II, crystalline Compound 1, orcrystalline Compound 2, and heating to form Form C. Preferably, thecrystalline form is heated at about 130° C. to about 145° C. for about30 to about 180 minutes. Small increases in temperature may have asignificant effect on the time required for the formation of Form C.

The invention also encompasses methods of preparing Form D comprisingproviding at least one of crystalline Compound 1, crystalline Compound2, or Form XIV, and drying the crystalline form at a pressure of lessthan about 100 mm Hg at 35° C. to form Form D.

The invention also encompasses methods of preparing a mixture ofcrystalline Compound 2 and crystalline Compound 1 comprising providingForm XI and drying at a pressure of less than about 100 mm Hg at 35° C.to form a mixture crystalline Compound 2 and crystalline Compound 1.

The invention also encompasses methods of preparing a mixture of Form D,crystalline Compound 1, and crystalline Compound 2 comprising providinga mixture of Form D and Compound 1, and drying the mixture at a pressureof less than about 100 mm Hg 35° C. to form a mixture of Form D,crystalline Compound 1, and crystalline Compound 2.

The invention also encompasses methods of preparing Form XII comprisingadding aripiprazole and ethanol (95% by volume) to form a mixture,heating the mixture at reflux until aripiprazole dissolves whilemechanically stirring the mixture at 12 rpm, filtering the mixture,cooling the mixture to 0° C. over 6 hours, stirring the mixture for onehour, filtering the mixture, and washing with one volume of ethanol (95%by volume). Form XII is obtained.

The invention also encompasses methods of preparing Form XX comprisingplacing Form XII into a fluidized bed dryer at about 30° C., leaving thematerial for about 3.5 hours at 30° C. to obtain a crystalline form, anddrying the crystalline form at about 40° C. until Form XX is formed.

Tables 1, 2, and 3 summarize the conversion of crystalline forms of theinvention.

The invention also encompasses pharmaceutical compositions comprisingaripiprazole crystalline forms of the invention. As used herein, theterm “pharmaceutical compositions” includes tablets, pills, powders,liquids, suspensions, emulsions, granules, capsules, suppositories, orinjection preparations. Pharmaceutical compositions containing thearipiprazole crystalline forms of the invention may be prepared by usingdiluents or excipients such as fillers, bulking agents, binders, wettingagents, disintegrating agents, surface active agents, and lubricants.Various modes of administration of the pharmaceutical compositions ofthe invention can be selected depending on the therapeutic purpose, forexample tablets, pills, powders, liquids, suspensions, emulsions,granules, capsules, suppositories, or injection preparations.

Any excipient commonly known and used widely in the art can be used inthe pharmaceutical composition. Carriers used include, but are notlimited to, lactose, white sugar, sodium chloride, glucose, urea,starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid,and the like. Binders used include, but are not limited to, water,ethanol, propanol, simple syrup, glucose solutions, starch solutions,gelatin solutions, carboxymethyl cellulose, shelac, methyl cellulose,potassium phosphate, polyvinylpyrrolidone, and the like. Disintegratingagents used include, but are not limited to, dried starch, sodiumalginate, agar powder, laminalia powder, sodium hydrogen carbonate,calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodiumlaurylsulfate, monoglyceride of stearic acid, starch, lactose, and thelike. Disintegration inhibitors used include, but are not limited to,white sugar, stearin, coconut butter, hydrogenated oils, and the like.Absorption accelerators used include, but are not limited to, quaternaryammonium base, sodium laurylsulfate, and the like. Wetting agents usedinclude, but are not limited to, glycerin, starch, and the like.Adsorbing agents used include, but are not limited to, starch, lactose,kaolin, bentonite, colloidal silicic acid, and the like. Lubricants usedinclude, but are not limited to, purified talc, stearates, boric acidpowder, polyethylene glycol, and the like. Tablets can be further coatedwith commonly known coating materials such as sugar coated tablets,gelatin film coated tablets, tablets coated with enteric coatings,tablets coated with films, double layered tablets, and multi-layeredtablets.

When shaping the pharmaceutical composition into pill form, any commonlyknown excipient used in the art can be used. For example, carriersinclude, but are not limited to, lactose, starch, coconut butter,hardened vegetable oils, kaolin, talc, and the like. Binders usedinclude, but are not limited to, gum arabic powder, tragacanth gumpowder, gelatin, ethanol, and the like. Disintegrating agents usedinclude, but are not limited to, agar, laminalia, and the like.

For the purpose of shaping the pharmaceutical composition in the form ofsuppositories, any commonly known excipient used in the art can be used.For example, excipients include, but are not limited to, polyethyleneglycols, coconut butter, higher alcohols, esters of higher alcohols,gelatin, and semisynthesized glycerides.

When preparing injectable pharmaceutical compositions, solutions andsuspensions are sterilized and are preferably made isotonic to blood.Injection preparations may use carriers commonly known in the art. Forexample, carriers for injectable preparations include, but are notlimited to, water, ethyl alcohol, propylene glycol, ethoxylatedisostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acidesters of polyoxyethylene sorbitan. One of ordinary skill in the art caneasily determine with little or no experimentation the amount of sodiumchloride, glucose, or glycerin necessary to make the injectablepreparation isotonic.

Additional ingredients, such as dissolving agents, buffer agents, andanalgesic agents may be added. If necessary, coloring agents,preservatives, perfumes, seasoning agents, sweetening agents, and othermedicines may also be added to the desired preparations.

The amount of aripiprazole or salt thereof contained in a pharmaceuticalcomposition for treating schizophrenia should be sufficient to treat,ameliorate, or reduce the symptoms associated with schizophrenia.Preferably, aripiprazole is present in an amount of about 1% to about70% by weight, and more preferably from about 1% to about 30% by weightof the dose.

The pharmaceutical compositions of the invention may be administered ina variety of methods depending on the age, sex, and symptoms of thepatient. For example, tablets, pills, solutions, suspensions, emulsions,granules and capsules may be orally administered. Injection preparationsmay be administered individually or mixed with injection transfusionssuch as glucose solutions and amino acid solutions intravenously. Ifnecessary, the injection preparations may be administeredintramuscularly, intracutaneously, subcutaneously or intraperitoneally.Suppositories may be administered into the rectum.

The dosage of a pharmaceutical composition for treating schizophreniaaccording to the invention will depend on the method of use, the age,sex, and condition of the patient. Preferably, aripiprazole isadministered in an amount from about 0.1 mg/kg to about 10 mg/kg of bodyweight/day. More preferably, about 1 mg to 200 mg of aripiprazole may becontained in a dose.

The invention also encompasses methods of making a pharmaceuticalformulation comprising adding at least one of aripiprazole crystallinecompound 1, crystalline Form I, II, VI, VIII, X, XI, XII, XIV, XIX, orXX, and a pharmaceutically acceptable excipient. As used herein, theterm “pharmaceutical formulations” includes tablets, pills, powders,liquids, suspensions, solutions, emulsions, granules, capsules,suppositories, or injection preparations.

Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther defined by reference to the following examples describing indetail the analysis of the aripiprazole crystalline forms and methodsfor preparing the crystalline forms of the invention. It will beapparent to those skilled in the art that many modifications, both tomaterials and methods, may be practiced without departing from the scopeof the invention.

EXAMPLES

X-ray powder diffraction data were obtained using a SCINTAG powder X-raydiffractometer model X'TRA equipped with a solid state detector andcopper radiation of 1.5418 Å. A round aluminum sample holder with zerobackground was used. All peak positions are within ±0.2 degrees twotheta. Differential scan calorimetry (DSC) analysis was performed usinga Mettler 821 Stare differential scanning calorimeter. The weight of thesamples was about 3 mg to about 6 mg. The samples were scanned at a rateof 10° C./min from 30° C. to at least 200° C. The oven was constantlypurged with nitrogen gas at a flow rate of 40 ml/min. Standard 40 μlaluminum crucibles covered by lids with 3 holes were used.

Thermogravimetric analysis (TGA) was performed using a Mettler M3thermogravimeter. The samples weighed about 10 mg and were scanned at arate of 10° C./min from 25° C. to 200° C. The oven was constantly purgedwith nitrogen gas at a flow rate of 40 ml/min. Standard 150 μl aluminacrucibles covered by lids with 1 hole were used.

Karl Fisher analysis was performed according to methods well known inthe art.

Example 1 Preparation of Aripiprazole Polymorphs

Aripiprazole (4 g) was dissolved in solvent in a round bottomed flask(50-250 ml), and heated to the lower of the solvent's boiling point orto aripiprazole's melting point and stirred until the aripiprazole fullydissolved. The immersion obtained was cooled to room temperature, andthen left at 4° C. for 15 hours. The precipitated crystalline form wascollected by filtration and studied by X-Ray Diffraction Technique(XRD). The crystalline form was then dried under reduced pressure ofless than about 100 mm Hg at 35° C. and again studied by XRD. Theresults are summarized in Table 1.

TABLE 1 Crystallization of Aripiprazole Crystalline forms Using Method 1Wet Resulting Volume (w)/ Crystalline Solvent/s (ml) Temp. (° C.) Dry(d) Form^(d) Dichloromethane 19 40 w X d I Chloroform 5 61 w II d IITetrahydrofuran 6 66 w II d II 1-Bromopropane 32 71 w Compound 2 dCompound 2 Methylethylketone 17 80 w Compound 1 + Compound 2 d Compound2 Trichloroacetonitrile 8 83-84 w I d I Dibromomethane 5 96-98 w XI dCompound 1 + Compound 2 1,4-Dioxane 6 100-102 w Compound 1 + Compound 2d hydrate + compound 2 Diethylamine 110 55 w II d II Acetone 90 56 w IId II Ethyl acetate 45 77 w Compound 1 + Form D d Compound 1 + Form D2-Propanol 80 82 w Compound 1 + Form D d Compound 1 + Form D + Compound2 Acetonitrile 165 81-82 w II d II Piperidine 4 106 w II d II + Compound2 Isobutanol 4 108 w Compound 1 d D Toluene 4 110.6 w Compound 1 +Compound 2 d Compound 2 Cyclopropylmethyl 3 114 w Compound 1 + ketoneCompound 2 d Compound 1 + Form D Pyridine 4 115-116 w XIV d Form D1-Butanol 8 118 w Compound 1 d Compound 1 + Compound 2 Isobutylmethyl 7116.5 w Compound 1 + ketone Compound 2 d Compound 2 Butylacetate 4124-126 w II d II Xylene 3 132 w Form D d Form D DMF 5 132 w II d IICyclohexanone 3 132 w Compound 1 d Form D Bromobenzene 4 132 w Compound1 d Compound 2 3-Amino-1-propanol 5.5 132 w Compound 2 d Compound 2Dimethylsulfoxide 4 132 w VIII d VIII Propylene glycol 3 132 w VI d VIChlorobenzene 4 132 w Compound 1 + Form D d D Cyclohexanamide 3.5 134 wCompound 1 + Form D d D 2-Dimethylamino 4 132 w Compound 1 + ethanolCompound 2 d Form D 1,2-Diaminoethane 4 118 w Form D d Form D Hexylamine4 131-132 w Compound 1 + Compound 2 d Compound 2 1,4-Dibromobutane 4 132w Am + Form D d Am + Form D Ethanol 68 78 w XII* d XII* Ethanol 95% in80 78 d XII* water Ethanol 80% in 160 78 w Compound 1 water d Compound 1Acetone^(b) 90 56 w II > Form D Chloroform^(b) 10 61 w Form D d Form DEthyl Acetate^(b) 50 77 d Compound 2 10 110.6 d Compound 2^(a)Aripiprazole MP = 132° C. ^(b)Solvent was immediately evaporatedafter aripiprazole's dissolution. ^(c)Traces of Form B were present.^(d)“Compound 1” is “crystalline Compound 1” and “Compound 2” is“crystalline Compound 2.” *Form XII may be characterized by X-ray powderdiffraction peaks at 17.4, 18.2, 19.7, and 24.5 degrees two-theta, ±0.2degrees two-theta as depicted in the XRD of FIG. 7.

Example 2 Preparation of Aripiprazole Crystalline Forms Using Co-SolventSystems

Aripiprazole (4 g) was dissolved in a given solvent in a round bottomedflask (50-250 ml), and heated to the solvent's boiling point untilaripiprazole fully dissolved. The temperature was cooled to the boilingpoint of the co-solvent to be used if this temperature was lower thanthe boiling point of the solvent used to dissolve aripiprazole. If aprecipitate formed during cooling, then additional solvent was addeduntil the precipitate dissolved. Co-solvent was then added until aprecipitate formed.

The immersion obtained was cooled to room temperature, and left at 4° C.for 15 hours. The resulting crystalline form was collected by filtrationand studied by XRD. The crystalline form was then dried under reducedpressure of less than about 100 mm Hg at 35° C. and again studied byXRD. The results are summarized in Table 2.

TABLE 2 Crystallization of Aripiprazole Crystalline forms by Method 2Resulting Volume Temp. Volume Wet (w)/ Crystalline Solvent (ml) (° C.)Co-Solvent (ml) dry(d) Form Ethyl Acetate 45 77 Methanol 12  w XII* dXII* Ethyl Acetate 45 77 Ethanol 50^(a ) w XIX d XIX Methylethyl 22 80Acetone   2.5 w Compound 2 ketone d Compound 2 Methylethyl 25 80Methanol 7 w XIX ketone d XIX Methylethyl 17 80 Ethanol 75  w Compound 1ketone d Compound 1 Methylethyl 17 80 Water 3 w XII* ketone d XII*Chloroform 5 61 Ether 1 w Compound 1 d Form D Chloroform 5 61 Acetone 2w Compound 2 d Compound 2 Chloroform 5 61 Methanol 3 w XIX d XIXChloroform 5 61 Ethanol 16  w XII* d XII* THF 16 66 Ether 10  w II d IITHF 6 66 Acetone 7 w II d II THF 7 66 Methanol 3 w XIX d XIX THF 6 66Ethanol 21  w XII* d XII* THF 6 66 2-Propanol 8 w II d II THF 6 66 Water1 w Compound 1 d II ^(a)Solvent B did not form a precipitate at thereflux temperature. ^(b)“Compound 1” is “crystalline Compound 1” and“Compound 2” is “crystalline Compound 2.” *Form XII may be characterizedby X-ray powder diffraction peaks at 17.4, 18.2, 19.7, and 24.5 degreestwo-theta, ±0.2 degrees two-theta as depicted in the XRD pattern of FIG.7.

Example 3 Preparation of Aripiprazole Crystalline Forms by Conversion

An aripiprazole crystalline form was heated to about 100° C. to about145° C. for about 30 to about 180 minutes until another crystalline formwas formed. The resulting crystalline form was analyzed using X-raydiffraction. The results are summarized below.

TABLE 3 Conversion of Aripiprazole Crystalline forms Initial HeatingConditions Resulting Crystalline Temp. Time Crystalline Form (° C.)(min) Form^(a) II 130 180 Form C Form D 130 60 Compound 2 + VII X 100 60Compound 2 XI 100 60 Compound 2 XI 130 60 Compound 2 XII 100 60 Compound2 XII 130 60 Compound 2 Compound 1 135 30 Form C Compound 130 30Compound 2 1 + Form D XIX 130 30 Compound 2 Compound 2 145 30 Form C^(a)“Compound 1” is “crystalline Compound 1” and “Compound 2” is“crystalline Compound 2.”

Example 4 Preparation of Crystalline Form II by Triturating in Acetone

Aripiprazole crystalline Compound 2 (3 g) and acetone (9 mol) were addedto a round bottomed flask equipped with a magnetic stirrer. The slurrywas stirred at room temperature for 5 hours until a precipitate formed.The precipitate was then isolated and identified as Form II. The Form IIwas dried at 50° C. overnight.

Example 5 Preparation of Form XII* by Crystallization in Ethanol

Aripiprazole (30 g) and ethanol (300 ml of 95% by volume) were added toa 1 liter reactor equipped with a mechanical stirrer, forming a mixture.The mixture was heated at reflux until aripiprazole dissolved, andmechanically filtered. The resulting solution was cooled to 0° C. over aperiod of 6 hours, and thereafter stirred for one hour. The solution wasthen filtered and washed with ethanol (one volume of 95% ethanol byvolume) to obtain Form XII.

Example 6 Preparation of Form XX by Drying Form XII*

Form XII (24 g) was dried in a fluidized bed dryer at 30° C. for 3.5hours. The material was then dried at 40° C. for 1.5 hours until Form XXwas obtained.

Example 7 Preparation of Crystalline Compound 2 by Drying Form XII*

Form XII (30 g) was dried in a 250 ml round-bottom 3-neck flask equippedwith a mechanical stirrer at 30° C. under reduced pressure of 60 mm Hgor less. After stirring for 3 hours at 30° C., the material was stirredat 40° C. for two hours, then at 70° C. for 5 hours, and finally at 90°C. for three hours. Crystalline Compound 2 was obtained.

Example 8 Preparation of Crystalline Compound 2 by Drying Form XII*

Form XII (30 g) was dried in a 0.25 L reactor equipped with a mechanicalstirrer at 30° C. under reduced pressure of 20 mm Hg or less. Afterstirring for 3 hours, the material was stirred at 40° C. for two hours,then at 70° C. for 5 hours, and finally at 90° C. for three hours.Crystalline compound 2 was obtained.

Example 9 Preparation of Crystalline Compound 2 by Drying Form XII*

Aripiprazole Form XII (35 g) was added to a 0.25 liter reactor equippedwith a mechanical stirrer at room temperature under reduced pressure of60 mm Hg or less. The temperature was increased gradually during 1 hourto 100° C., and maintained at 100° C. for 1 hour. Crystalline Compound 2was obtained.

Example 10 Preparation of Crystalline Compound 2 by Drying Form XII*

Form XII (28 g) was dried in a 0.25 L reactor equipped with a mechanicalstirrer at 30° C. under reduced pressure of 60 mm Hg or less. Afterstirring for 3 hours, the material was stirred at 40° C. for 2.5 hours,then at 70° C. for 5 hours, and finally at 90° C. for 8 hours.Crystalline Compound 2 was obtained. * Form XII may be characterized byX-ray powder diffraction peaks at 17.4, 18.2, 19.7, and 24.5 degreestwo-theta, +0.2 degrees two-theta as depicted in the XRD pattern of FIG.7.

1. A method of preparing Form II by slurrying crystalline Compound 2 inacetone until Form II is formed.
 2. The method of claim 1, whereincrystalline Compound 2 is slurried in acetone for about one to about 24hours.
 3. The method of claim 1, wherein crystalline Compound 2 isslurried in acetone for about three to about 24 hours.
 4. The method ofclaim 1, wherein crystalline Compound 2 is slurried in acetone for aboutfive hours.
 5. The method of claim 1, wherein Form II has an averagesize of about 300 microns or less.
 6. The method of claim 1 furthercomprising drying the Form II at about 50° C.
 7. A method of preparingat least one of crystalline Compound 1, crystalline Compound 2, Form D,Form I, Form II, Form VI, Form VIII, Form X, Form XI, or Form XIIcomprising: dissolving aripiprazole in a solvent to form a mixture,heating the mixture to between about 40° C. and about 132° C.; coolingthe mixture until at least one of aripiprazole crystalline compound 1,crystalline compound 2, crystalline Form I, II, VI, VIII, X, XI, or XIIprecipitates; and collecting the aripiprazole.
 8. The method of claim 7,wherein aripiprazole is dissolved in a solvent comprising at least oneof C₃₋₆ ketones, C₁₋₆ nitrites, C₁₋₄ alcohols, C₁₋₆ halogenated alkanes,C₁₋₆ amines, C₂₋₆ amides, C₂₋₆ esters, C₂₋₆ ethers, C₁₋₆ sulfoxides, orC₄₋₁₀ aromatics.
 9. The method of claim 8, wherein aripiprazole isdissolved in a solvent comprising at least one of acetone, acetonitrile,trichloroacetonitrile, methanol, ethanol, n-propanol, isobutanol,propylene glycol, methylethylketone, tetrahydrofuran, DMF, piperidine,pyridine, xylene, toluene, cyclohexanamide, diethylamine, hexylamine,dimethylsulfoxide, ethyl acetate, butyl acetate, dichloromethane,dibromomethane, chloroform, 1-bromopropane, 1,4-dioxane,1,2-diaminoethane, 1,4-dibromobutane, isopropanol, 1-butanol,2-dimethylaminoethanol, cyclopropylmethylketone, orisobutlymethylketone.
 10. A method of preparing crystalline Compound 2,comprising: dissolving aripiprazole in a solvent to form a mixture,heating the mixture to about 40° C. to about 132° C., cooling themixture until crystalline compound 2 precipitates, and collecting theprecipitated crystalline compound
 2. 11. The method of claim 10, whereinaripiprazole is dissolved in a solvent comprising at least one of C₃₋₆ketones, C₁₋₆ nitriles, C₁₋₄ alcohols, C₁-6 halogenated alkanes, C₁₋₆amines, C₂-6 amides, C₂₋₆ esters, C₂₋₆ ethers, C₁₋₆ sulfoxides, andC₄₋₁₀ aromatics.
 12. The method of claim 11, wherein aripiprazole isdissolved in a solvent comprising at least one of chloroform,tetrahydrofuran, diethylamine, acetone, acetonitrile, piperidine,butylacetate, or DMF.
 13. The method of claim 7 or 10, wherein themixture of aripiprazole and solvent is heated to the lower of about theboiling point of the solvent or aripiprazole's melting point.
 14. Themethod of claim 7 or 10, wherein the cooling step is carried out at atemperature of about 4° C.
 15. The method of claim 14, wherein thecooling step is carried out for about 15 hours.
 16. The method of claim7 or 10 further comprising drying the aripiprazole precipitate.
 17. Amethod of preparing at least one of aripiprazole crystalline compound 1,crystalline compound 2, crystalline form D, II, XII or XIX, comprising:dissolving aripiprazole in a solvent to form a mixture, heating themixture to the solvent's boiling point until aripiprazole dissolves,cooling the mixture, adding a co-solvent to the mixture of aripiprazoleand solvent until at least one of aripiprazole crystalline compound 1,crystalline compound 2, crystalline Form D, II, XII, or XIXprecipitates, and collecting the aripiprazole.
 18. The method of claim17, wherein the solvent used is at least one of the group comprisingC₂₋₆ esters, C₂₋₆ ethers, methylethylketones, or C₁₋₆ halogenatedalkanes.
 19. The method of claim 18, wherein the solvent used is atleast one of ethyl acetate, methylethylketone, chloroform, ortetrahydrofuran.
 20. The method of claim 17, wherein the co-solvent isat least one of water, C₁₋₄ alcohol, ether, or acetone.
 21. The methodof claim 20, wherein the co-solvent is at least one of water, methanol,ethanol, acetone, ether, or 2-propanol.
 22. A method of preparingaripiprazole crystalline form II comprising: providing aripiprazolecrystalline compound 1; and drying the aripiprazole to obtainaripiprazole crystalline form II.
 23. The method of claim 22, whereinthe drying step is performed at a temperature of about 35° C.
 24. Themethod of claim 22, wherein the drying step is performed at a pressureof less than about 100 mm Hg